title: FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice.
abstract: BACKGROUND
  FK506 binding protein (FKBP)12 is a known cis-trans peptidyl prolyl isomerase and highly expressed in the heart. Its role in regulating postnatal cardiac function remains largely unknown.
  
  
  RESULTS
  We generated FKBP12 overexpressing transgenic (αMyHC-FKBP12) mice and cardiomyocyte-restricted FKBP12 conditional knockout (FKBP12(f/f)/αMyHC-Cre) mice and analyzed their cardiac electrophysiology in vivo and in vitro. A high incidence (38%) of sudden death was found in αMyHC-FKBP12 mice. Surface and ambulatory ECGs documented cardiac conduction defects, which were further confirmed by electric measurements and optical mapping in Langendorff-perfused hearts. αMyHC-FKBP12 hearts had slower action potential upstrokes and longer action potential durations. Whole-cell patch-clamp analyses demonstrated an ≈ 80% reduction in peak density of the tetrodotoxin-resistant, voltage-gated sodium current I(Na) in αMyHC-FKBP12 ventricular cardiomyocytes, a slower recovery of I(Na) from inactivation, shifts of steady-state activation and inactivation curves of I(Na) to more depolarized potentials, and augmentation of late I(Na), suggesting that the arrhythmogenic phenotype of αMyHC-FKBP12 mice is attributable to abnormal I(Na). Ventricular cardiomyocytes isolated from FKBP12(f/f)/αMyHC-Cre hearts showed faster action potential upstrokes and a more than 2-fold increase in peak I(Na) density. Dialysis of exogenous recombinant FKBP12 protein into FKBP12-deficient cardiomyocytes promptly recapitulated alterations in I(Na) seen in αMyHC-FKBP12 myocytes.
  
  
  CONCLUSIONS
  FKBP12 is a critical regulator of I(Na) and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of I(Na) may underlie clinical arrhythmias associated with FK506 administration.
authors.affiliation: Department of Medicine, University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Bai-Yan
authors.initials: BY
authors.lastname: Li
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Xuehong
authors.initials: X
authors.lastname: Xu
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Zhu
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Guixue
authors.initials: G
authors.lastname: Bu
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: W Jonathan
authors.initials: WJ
authors.lastname: Lederer
authors.forename: John H
authors.initials: JH
authors.lastname: Schild
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D006329:Heart Conduction System / Q000502:physiology*; D066298:In Vitro Techniques; D019426:Integrases / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology*; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D015222:Sodium Channels; C045073:Cre recombinase; D019426:Integrases; D022061:Tacrolimus Binding Protein 1A; D002118:Calcium